Introduction to biomaterials for wound healing

Introduction to biomaterials for wound healing

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P. Aramwit Chulalongkorn University, Phatumwan, Bangkok, Thailand

  

1.1  Definition of biomaterial Biomaterial by definition is “a non-drug substance suitable for inclusion in systems which augment or replace the function of bodily tissues or organs” (Nicolai and Rakhorst, 2008). These materials are capable of being in contact with bodily fluids and tissues for prolonged periods, while eliciting minimal if any adverse reactions (Heness and Ben-Nissan, 2004). In this sense, biomaterials are classified as synthetic or natural substances. Hence, in this chapter a biomaterial is defined as any substance (other than a drug) or combination of substances, synthetic or natural in origin, which can be used as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body (von Recum and LaBerge, 1995). The field of biomaterials working under biological constraints is rapidly expanding and represents 2–3% of the overall health expenses in developed countries. This field covers many different materials: cardiac artificial valves; artificial vessels; cardiac stimulators; stents; artificial hips, knees, shoulders, and elbows; materials for internal fracture fixation; scoliosis treatment; materials for urinary tract reconstruction; artificial crystalline lenses; skin; ear ossicles; and dental roots (Sedel, 2004).

1.2  Types of biomaterials Since the introduction of sutures for wound closure (Davis, 2003), the use of biomaterials has expanded intensively. Biomaterials can be divided into synthetic or natural.

1.2.1   Synthetic biomaterials The most common synthetic biomaterials used for implants are titanium, silver products, polyester, and porcelain. Synthetic biomaterials can be divided into the following four categories (Agrawal, 1998).

1.2.1.1   Metals Metals are the most widely used for load-bearing implants such as artificial joints for hips and knees. Although many metals and alloys are used for medical device Wound Healing Biomaterials - Volume 2. http://dx.doi.org/10.1016/B978-1-78242-456-7.00001-5 Copyright © 2016 Elsevier Ltd. All rights reserved.

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Wound Healing Biomaterials

applications, the most commonly used metals are stainless steel, pure titanium, and titanium alloys.

1.2.1.2  Polymers Polymers are widely used for several applications such as facial prostheses, tracheal tubes, and kidney and liver parts. They are also used for medical adhesives and sealants or for coating of other materials to modify their function. Polyester, polytetrafluoroethylene, and polyurethane are the most commonly used biomaterials for artificial devices. According to US Food and Drug Administration standards, these polymers are considered biocompatible biomaterials. The biocompatibility response of synthetic biomaterials in vivo is signified by hydrolysis via inflammatory cells and by the formation of a fibrous capsule that is the body’s response to a foreign intruder (Mathur et al., 1997; Anderson et al., 1998). In practice the biocompatibility of a material is defined by its ability to fill space and assist the body in regenerating tissue to develop permanent solutions to reconstruction and to reduce abnormal chronic wound healing (Mathur, 2009). The newer biodegradable biomaterials, including polylactic acid (PLA) and polyglycolic acid (PGA), also have a polyester chemistry, and they are degraded by hydrolysis that results in large amounts of by-products that lower the pH of the local microenvironment. This may influence wound healing (Mathur, 2009). PGA provides a biocompatible surface for the cells to proliferate and has been widely used for tissue engineering of artificial arteries. PGA does not provide a mechanically robust matrix which would enable the cells to withstand the in vivo shear and compressive loads, and it also results in dedifferentiation of cells (Higgins et al., 2003). Polyethylene glycol (PEG) lacks the chemistry for cellular interface unless ligand-presenting entities are introduced (Gobin and West, 2003). Classical tissue engineers prepared a cell-seeded biomimetic hydrogel such as ligand-modified PEG and studied the cell response by measuring proliferation and differentiation (Gobin and West, 2003). In this situation, most cells can adhere to the adhesion ligands and secrete a protease whose cleavage sequence is incorporated within the gel, which renders the hydrogel completely nonresponsive. From this case, the gel has all the characteristics of a synthetic nondegradable biomaterial and only two characteristics out of many of being a biologically responsive biomaterial. This indicates that cells need multiple signals in a tissue-engineered scaffold to mimic their in vivo behavior (Mathur, 2009).

1.2.1.3  Ceramics Ceramic is primarily used as a restorative material in dentistry. Due to its poor fracture toughness, other uses are limited.

1.2.1.4  Composites Composite materials are used extensively for prosthetic limbs wherein their low density/weight and high strength make them ideal materials for prosthetic applications.

Introduction to biomaterials for wound healing

Table 1.1 

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Biomaterials for medical applications

Biomaterial

Advantages

Disadvantages

Examples

Metal

Strong, tough, and ductile

Corrodible, dense, and complicated to fabricate

Polymers

Resilient and easy to fabricate

Fragile, deformable, and degradable

Ceramics

Very biocompatible, inert, and strong in compression Strong in compression

Difficult to fabricate, brittle, and not resilient Difficult to fabricate

Joint replacement, bone plates and screws, dental root implants, pacers, and sutures Blood vessels; sutures; tissue engineering for ear, nose, and soft tissues Dental coatings and orthopedic implants, such as femoral head of neck Joint implants, heart valves

Composites

The advantages and disadvantages of each biomaterial category are shown in Table 1.1.

1.2.2   Natural biomaterials Natural biomaterials are derived from animals, microbials, or plants. One advantage of natural biomaterials is that they are similar to materials familiar to the body (Davis, 2003). In this regard the field of biomimetics, or mimicking nature, is growing. There is seldom a toxicity issue with the use of natural materials in contrast to synthetic materials. Moreover, natural biomaterials may carry specific protein binding sites and other biochemical signals that may assist in tissue healing or integration. The major concerns of using these materials are immunogenicity and decomposition at temperatures below their melting points. This severely limits their fabrication into implants of different sizes and shapes (Ige et al., 2012). Natural biomaterials are typically similar to macromolecular substances which are prepared for metabolic pathways. As a result, the problems of toxicity and simulation of a chronic inflammatory reaction which is provoked by many synthetic polymers are suppressed (Ige et al., 2012). Moreover, natural biomaterials are degradable. There is also a capability for designing these biomaterials at molecular rather than macroscopic levels. Some advantages and disadvantages of natural biomaterials are presented in Table 1.2. Until now, no biomaterials were considered as “responsive” to the cell. In essence, from the initial inflammatory reaction of the body to scar formation, wound healing is controlled by cellular reactions to the biomaterial. A responsive biomaterial would have a topography, architectural assembly, biomolecular composition, and chemistry that would give a cell control of the biomaterial at the cell–material interface, which is a physical link that the cell has with the biomaterial as the cell adheres and migrates through the biomaterial. Cytokine production, growth factor release, and other chemical mediators that are released by the cell are controlled in a feedback loop at the cell–substrate interface (Miranti and Brugge, 2002).

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Table 1.2  Advantages

and disadvantages of natural biomaterials

(Lujan, 2010) Advantages

Disadvantages

No toxicity or foreign body response

Immunological reaction, body’s immune system recognizes foreign materials for ultimate inactivation/elimination High natural variability Structurally more complex than traditional materials; technological manipulation is more complicated

Function biologically at molecular level Natural degradation can occur in the body via natural enzymes; cross-linking delays this process

1.3  Wound healing Healthy skin, bone, and muscle undergo in situ self-healing that prevents the accumulation of defects from tissue aging and fatigue (Brochu et al., 2011). Healing and biomaterials are most commonly linked through the tissue response to an implant (Kindt et al., 2007). Wound healing is divided into inflammation, proliferation, and remodeling (Fig. 1.1). Various studies have aimed at modulating inflammation and proliferation. Even though inflammation is a common event in allergic diseases, autoimmune diseases, infectious diseases, and others, it is essential for proper healing (Kasuya and Tokura, 2014). The objective of wound management is to heal the wound in the shortest time to prevent infection and minimize pain, discomfort, and scarring. The successful treatment of a wound should ensure that the amount of necrotic tissue is reduced and that microbial invasion is prevented (Mayet et al., 2014). Traditional wound management used simple materials such as gauze according to the principle “to cover and conceal.” More recent developments have taken advantage of the deeper understanding of the underlying molecular and cellular mechanisms. Ensuring that the pharmacological, pharmacokinetic, and mechanical requirements of wound healing are met will provide a novel approach to remove the barriers to natural healing and enhance the effects of advanced therapies (Schultz et al., 2004). The need for effective methods or biomaterials is especially urgent for large or complicated wounds. Creative ideas will promote novel opportunities for tissue regeneration and repair (Mayet et al., 2014). To ensure maximal benefit of advanced treatments the TIME algorithm was introduced, with the main purposes being to assess and restore the biochemical environment (Schultz et al., 2004; Granick et al., 2006): T—Deficient and nonviable tissues impede the migration of keratinocytes across the wound bed and act as a focus for infection. I—Uncontrolled inflammation and infection may perpetuate a cycle of repeated injury and insult to the wound area that should be corrected for optimal cell functionalities. M—Excess moisture may result in maceration of the wound bed and surrounding tissue, whereas wound desiccation may impede the wound healing process. E—The migrating epithelial edge is a sign that healing is taking place, whereas a nonmigrating edge indicates poor healing.

Introduction to biomaterials for wound healing

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Inflammatory phase Molecules

Increase of vascular permeability Damage of skin constituent cells

DAMPs, PAMPs Cytokines Chemokines HMGB1

Operation of innate immunity Infiltration of neutrophils and macrophages Proliferation phase

Signaling

Fibroplasia, ECM formation

TGF-β/Smad signaling

Angiogenesis

Wnt/β-catenin signaling

Reepithelialization

Other signaling pathways

Remodeling

Figure 1.1  Phases and factors involved in the wound healing process divided into inflammation, proliferation, and remodeling. Multiple factors and signaling pathways operate codependently. DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; HMGB1, high-mobility group box 1; ECM, extracellular matrix; TGF-β, transforming growth factor-β. Reprinted with permission from publisher: Kasuya, A., Tokura, Y., 2014. Attempts to accelerate wound healing. J. Dermatol. Sci. 76 (3), 169–172.

Modern dressings are designed to provide functional and desirable characteristics, which include debridement activity, moist wound environment, low adherence, protection from trauma, minimal dressing changes, thermal insulation, absorption of excess exudate and blood at the wound site, infection and bacterial invasion protection, adequate gaseous exchange, and cost effectiveness. In addition, dressings should be free of toxins and infectious agents, easily placed and replaced, and aid wound drainage (Brown-Etris et al., 2002). Several types of wound materials have been developed to fulfill these prerequisites and can be classified into three categories (Freyman et al., 2001): 1. traditional dressings 2. biomaterial-based dressings 3. artificial dressings

1.3.1   Traditional dressings The main functions these dressings perform are to stop bleeding and protect the wound (Sheridan and Tompkins, 1999). The best example of this group is cotton gauze (Sezer and Cevher, 2011). Gauze has several disadvantages, including damaging newly formed epithelium upon removal and causing rapid dehydration of the wound bed (Naimer and Chemla, 2000; Siritientong et al., 2014). Therefore gauze composites with a nonadherent wound contact material have been developed. Another significant

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Wound Healing Biomaterials

problem of this dressing type is the leakage of exudate, which may increase the risk of infection (Sezer and Cevher, 2011). Antibacterial agents are therefore added to minimize the infection risk. In addition, foreign body reactions to the cotton fibers are sometimes observed (Lim et al., 2000; Price et al., 2001), although this is rare (Ågren et al., 2006). The low cost is the major reason for their popularity.

1.3.2  Biomaterial-based dressings The most convenient method to achieve complete wound closure is autografting. Inadequate donor areas for large wounds have led to the search for new tissue sources (Sheridan et al., 2001). Biological dressings are typically made of collagen-type structures with elastin and lipids (Sezer and Cevher, 2011). Such dressings are categorized as allografts or xenografts (Kearney, 2001; Sheridan et al., 2001). An allograft is a graft between individuals of the same species, but of different genotypes. The most common source is fresh or freeze-dried skin fragments from cadavers or a patient’s relatives. A xenograft is a graft between animals of different species (eg, between closely related species). The most common dressing is derived from pig skin. Although this type of dressing seems to give promising outcomes, advanced technologies are necessary to provide consistent materials and simple handling.

1.3.3  Artificial dressings The use of traditional dressing materials and biomaterial-based dressings is restricted due to stability problems and the associated risk of infection (Sezer and Cevher, 2011). Several attempts have been made to overcome these disadvantages. Variations in pathophysiology make it difficult to develop an artificial dressing that meets all the criteria for optimal healing. Synthetic and natural polymers are used for artificial dressings (Table 1.3).

1.4  Biomaterials used for dermal wound healing Contemporary biomaterials used in areas of reconstruction, repair, and artificial devices are not designed to regenerate tissue, but instead to cover or fill defects, perform a mechanical function, or both (Mathur, 2009). Materials or biologics that promote tissue formation, preserve volume and shape, and shorten the time of wound healing are needed. An ideal regenerative or responsive biomaterial recruits precursor cells to form new viable tissue in vivo and stimulates wound healing (Mathur, 2009). Although the biology and chemistry of healing have significant impacts on biomaterial performance, biological healing does not address the physical repair of biomaterials that experience mechanical and chemical breakdown as they are subjected to loading and degradation effects in vivo (Brochu et al., 2011). Developing biomaterials with the intrinsic ability to autonomously repair mechanical and chemical damage would be particularly important for implants that replace tissues that are also capable of self-repair.

Introduction to biomaterials for wound healing

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Table 1.3 

Examples of wound dressing types in the world market (Sezer and Cevher, 2011) Dressing material

Brand name

Traditional dressing Absorbent cotton pad Absorbent cotton fibers impregnated with polyhexamethylene biguanide Highly absorbent cotton wool pad Highly absorbent rayon/cellulose blend sandwiched with a layer of antishear high-density polyethylene Paraffin gauze dressing Paraffin gauze dressing containing 0.5% chlorhexidine acetate Petrolatum gauze containing 3% bismuth tribromophenate Scarlet red dressing Hydrogel dressing

Telfa® “Ouchless” nonadherent dressing Telfa AMD® Gamgee® pad Exu-Dry® dressing

Jelonet®, Adaptic® Bactigras® Xeroform® Scarlet Red® 2nd Skin®

Biomaterial-based dressing Porcine dermis

EZ Derm®

Artificial dressing Polypropylene film and polyurethane foam Silicone film with peptide-coated nylon fabric Polyurethane film dressing Hydroxylated polyvinyl alcohol foam Calcium alginate Polyhydroxyethylmethacrylate and polyethylene glycol 400 spray

Epigard® Biobrane® Opsite®, Tegaderm® Ivalon® Kaltostat® Hydron®

1.4.1  Synthetic biomaterials Synthetic biomaterials offer many advantages over natural biomaterials as they can be synthesized and modified in a controlled manner according to the specific requirements needed to produce constant and homogenous physical and chemical properties as well as stability (Zhong et al., 2010a).

1.4.1.1  Polyurethanes and their derivatives Polyurethanes are copolymers containing urethane groups. They are formed by conjugation of diol and diisocyanate groups (Trumble et al., 2002). Polyurethanes have been used extensively as biomaterials because of their biocompatibility, strength, and flexibility, for example, in catheters and gastric balloons. They are unstable in acidic environments (Pinchuk, 1994). An example of nontoxic polyurethanes used for treatment of burns and wounds is Pellethane® 2363-80A, which can accelerate epithelialization (Wright et al., 1998).

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Wound Healing Biomaterials

1.4.1.2  Teflon This polymer is synthesized from tetrafluoroethylene at high temperature and pressure. Teflon is noncarcinogenic, insoluble in polar and nonpolar solvents, and easily sterilized. Furthermore, its shape is easily modified using low pressure, resulting in a comfortable fit to the injured area (Lee and Worthington, 1999; Raphael et al., 1999).

1.4.1.3  Silicone Silicone is nontoxic, nonallergenic, and highly biocompatible (O’Donovan et al., 1999; Jansson and Tengvall, 2001). Silicone is resistant to biodegradation and can be used in the preparation of implant elastomers used in soft tissue repair and in the production of hypodermic needles and syringes (Van den Kerckhove et al., 2001). Moreover, it is often used as wound support material in severe burns and wounds, for scar treatment (Whelan, 2002; Losi et al., 2004), and as a nonadherent interface material in many dressings.

1.4.2  Natural biomaterials Natural biomaterials offer a therapeutic advantage as opposed to the inert synthetic biomaterials. The natural origins of these biomaterials make them suitable substitutes of the extracellular matrix (ECM) and original cellular environment of the native skin (Mayet et al., 2014). The emollient, demulcent, astringent, antimicrobial, antiinflammatory, and antioxidant properties of natural products may be beneficial for the wound healing process (Mogosanu et al., 2012). Natural polymers such as chitosan, collagen, elastin, and fibrinogen are biocompatible substrates that are similar to macromolecules recognized by the human body (Mogosanu and Grumezescu, 2014). They are also used in regenerative medicine for human epithelial stem cell culture or in vitro– reconstituted epithelia (Guerra et al., 2009). The limitations are batch-to-batch variability, heterogeneity, and high cost (Tabata, 2009). The normally low mechanical strength of natural macromolecules can be improved by cross-linking or blending with synthetic polymers, but at the expense of biocompatibility (Mogosanu and Grumezescu, 2014).

1.5  Polysaccharide-based biomaterial Polysaccharides are natural biomaterials which are inexpensive, and most of them are easily degradable. The majority (about 75%) of all organic material on earth is in the form of polysaccharides (Atala and Mooney, 1997). Polysaccharide-based biomaterials used for wound care can be classified into several categories: neutral (β-glucan, dextrans, cellulose), acidic (alginic acid, hyaluronic acid), basic (chitin, chitosan), or sulfated (heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate) (Kennedy et al., 2011).

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1.5.1   Homoglycans Polysaccharides that contain molecules of one sugar are called homopolysaccharides or homoglycans. They are naturally occurring biocompatible materials used locally to modulate the cellular responses during wound healing (Lloyd et al., 1998).

1.5.1.1   Starch Starch is one of the most abundant and cheapest polysaccharide. Natural starch occurs in a granular form. Generally starch consists of amylose (linear α-(1-4) glucan) and amylopectin (dendritically branched version) (Biliaderis, 1992). The content and ratio of amylose and amylopectin in starch vary depending on the source, and they have an effect on behavior during processing and the properties of the end product. Starch is insoluble in cold water, but is very hygroscopic and binds water reversibly. It is renewable and biodegradable, and it can be used as bone replacement implants and in bone cements, drug delivery systems, and tissue scaffolds (Pereira et al., 1998).

1.5.1.2   β-Glucans Different types of β(1→3)-d-glucans isolated from yeast, fungi, and grain were investigated for their immunological and pharmacological properties because of their ability to form single- and triple-helical resilient gel structures. Highly purified yeast-derived insoluble β(1→3)-d-glucan strongly inhibited adipogenic differentiation, supported wound healing, and significantly lowered skin irritation compared to cotton gauze (Huang and Yang, 2008; Lehtovaara and Gu, 2011).

1.5.1.3  Chitin and chitosan Chitin is the structural element in the exoskeleton of crustaceans, such as crabs and shrimps, and in the cell walls of fungi. Chitin is the most abundant natural amino polysaccharide (poly-N-acetyl-glycosamine) produced annually. It is a nitrogen-containing polysaccharide and related chemically to cellulose. The native chitin molecule has strong intermolecular and intramolecular hydrogen bonds with partial N-deacetylation (Hirano and Midorikawa, 1998). One disadvantage is its insolubility in common solvents and the difficulties related to chitin processing. Chitin is hemostatic, and it may enhance immunity and wound healing. Chitin is considered a nontoxic, nonallergenic biomaterial and is not rejected by the body. The biocompatibility, biodegradability, and adsorption properties of chitin and its derivatives are considerably higher than those of synthetically substituted cellulose (Ige et al., 2012). Chitosan, a moiety of glycosaminoglycans (GAGs), is a linear polysaccharide produced by deacetylation of chitin and composed of randomly distributed β-(1-4)-linked d-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit) (Muzzarelli and Muzzarelli, 2002). This biomaterial is common in the biomedical field due to its biocompatibility, low toxicity, and low thrombogenicity, although it causes red blood cell agglutination (Rao and Sharma, 1997).

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Wound Healing Biomaterials

Chitosan is biodegradable and the degradation rate decreases as the degree of deacetylation increases (Tomihata and Ikada, 1997). A chitosan membrane with a deacetylation degree of 73% was degraded 7 days after application to full-thickness skin excision in rats (Nordback et al., 2015). Chitosan supports the adhesion and activation of platelets (Lord et al., 2011). Moreover, chitosan has antimicrobial (Cho et al., 1999; Mi et al., 2002) and antiinflammatory activities (Han, 2005). Chitosan elicits minimal foreign body reactions and favors both soft and hard tissue regeneration (Jin et al., 2004). Chitosan is therefore used for wound treatment (Ueno et al., 1999; Khor and Lim, 2003; Senel and McClure, 2004). Paul and Sharma (2004) found that topical chitosan accelerated fibroblast proliferation and increased early phase reactions related to healing. Chitosan also promoted granulation tissue formation and remodeling of damaged tissues in large, open wounds (Ueno et al., 2001). It has been shown that a chitosan hydrogel interacts with fibroblast growth factor-2 in open wounds of diabetic mice. This interaction resulted in increased angiogenesis, granulation tissue, and wound closure rate (Obara et al., 2005). A bilayer chitosan membrane, consisting of an upper chitosan film layer attached to an inner layer of porous membrane, served as an efficient skin-regenerating template for treating third-degree burns and cutaneous wounds (Mao et al., 2003). The three-dimensional (3D) structural organization of chitosan is essential to serve as a vehicle for delivering and retaining the cells at a specific site and to initiate appropriate cell–cell interactions (Liao et al., 2010). Chitosan is also used as an intraocular lens material due to its oxygen permeability and has been evaluated for use in the bioremediation of toxic phenolic compounds (Beran et al., 2007).

1.5.1.4  Cellulose Wound dressings of modified cellulose can incorporate active molecules such as enzymes, growth factors, antimicrobial agents, antioxidants, hormones, vitamins, and other agents (Medusheva et al., 2007; Aramwit and Bang, 2014). Bacterial cellulose is synthesized by growing Acetobacter xylinum in various media such as coconut juice, pineapple juice, or any carbohydrate substrate. Bacterial cellulose is a versatile biomaterial with a unique nanostructure (Fig. 1.2), high mechanical strength, and remarkable swelling properties. As a natural biocompatible, biodegradable, antimicrobial, hypoallergenic, and nontoxic polymer, bacterial cellulose is an innovative natural polymeric raw material for wound dressing applications (Czaja et al., 2007; Muangman et al., 2011; Park et al., 2014). One major advantage of bacterial cellulose is its absorptive capacity of wound exudate which is the reason for the many composites of bacterial cellulose sheets impregnated with several active components. Carboxymethylcellulose (CMC) is widely used in dressings. It is a cellulose derivative with carboxymethyl groups (–CH2–COOH) bound to some of the hydroxyl groups of the glucopyranose monomers that make up the cellulose backbone. In contrast to cellulose, CMC is a hydrophilic polymer and thus solubilized in water, with excellent water swelling ability. Furthermore, CMC is biocompatible and shows low toxicity and immunogenicity. These characteristics make CMC an attractive constituent in food, cosmetics, and pharmaceuticals and for tissue engineering and drug delivery systems (Bajpai and Giri, 2003; Pasqui et al., 2014). CMC can be formulated as a “solid-like solution” or hydrogel. This biomaterial can be easily mixed with other polymers

Introduction to biomaterials for wound healing

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Figure 1.2  Fiber structure of cellulose from plant (left) and bacterial cellulose (right) under a scanning electron microscope. Magnification ×500. Scale = 50 μm.

such as chitosan, alginate, and polyvinyl alcohol, yielding products with favorable properties (Ågren, 1998; Bradford et al., 2009; Lee et al., 2010; Zhang et al., 2013).

1.5.2   Heteroglycans Heparin, hyaluronic acid (HA), and chondroitin sulfates are examples of heteroglycans which give sugar amine and sugar uronic acids (two different products), whereas starch gives only glucose (one product) and hence is homoglycan. Some heteroglycans exhibit important applications in biomedical areas, especially due to their biocompatibility, biodegradability, and peculiar physicochemical features (Rinaudo, 2008).

1.5.2.1  Alginic acid and its salts Alginic acid, also called algin or alginate, is an anionic polysaccharide distributed widely in the cell walls of brown algae, including Laminaria and Ascophyllum species. It is formed by linear block copolymerization of d-mannuronic acid and l-guluronic acid. Alginates are linear unbranched polysaccharides which contain different amounts of (1→4′)-linked β-d-mannuronic acid and α-l-guluronic acid residues. Alginate is biodegradable, has controllable porosity, and may be linked to other biologically active molecules. Interestingly, encapsulation of certain cell types into alginate beads may actually enhance cell survival and growth. Due to their hemostatic properties, alginate and its salts are used for wound treatment in various forms such as gel or sponge. Calcium alginate can also increase cellular activity properties such as adhesion and proliferation (Thomas, 2000a,b,c). Obtained from processed algae, calcium alginate, calcium–sodium alginate, collagen–alginate, and gelatin–alginate are highly absorbent natural fiber dressings (Qin et al., 2006; Thu et al., 2012). Alginate can absorb water and body fluids up to 20 times its weight, resulting in a hydrophilic gel. The formed gel is weak, but it maintains a moist wound healing environment.

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1.5.2.2  Glycosaminoglycans GAGs are important components of the ECM and are essential for skin and bone regeneration. The structure, polymer length, and degree of sulfation determine the attraction of skin and bone precursor cells (Salbach et al., 2012). Heparin-coated aligned nanofibers increase endothelial cell infiltration in 3D scaffolds and tissue remodeling in vitro and in vivo (Kurpinski et al., 2010). Heparan sulfate glycosaminoglycans (HS-GAGs) and OTR4120, a polymer engineered to mimic properties of HS-GAGs, were shown to decrease inflammation and stimulate angiogenesis and collagen maturation in wounds and burns (Tong et al., 2009).

1.5.2.3  Hyaluronic acid The extremely hydrophilic HA is a naturally occurring, nonimmunogenic, anionic, nonsulfated GAG distributed widely throughout connective tissues, epithelia, neural tissues, and synovial fluids. This biomaterial is abundant in skin, cockscomb, cartilage, and vitreous humor. HA consists of 2-acetamide-2-deoxy-α-d-glucose and β-d-gluconic acid residues linked by alternate (1,3) and (1,4) glycoside bonding, and it has a high capacity of lubrication, water sorption, and water retention and influences several cellular functions such as migration, adhesion, and proliferation (Lee et al., 2003). HA interacts with proteins, proteoglycans, growth factors, and tissue components which is of vital importance in wound healing (Park et al., 2003). HA has bacteriostatic activity (Miller et al., 2003). Due to the high density of negative charges along the polymer chain, HA adopts highly extended random coil conformations. HA is popular in the medical and bioengineering fields mainly because it degrades into simple sugars. HA has been used for wound healing (Neuman et al., 2015), tissue engineering, and ophthalmic surgery; as a component in implant materials in reconstructive plastic surgery; and for facial wrinkle and folds of the skin (Lee et al., 2003; Sparavigna et al., 2014; Zhang et al., 2015a). Moreover, HA is used for lubrication of joints in osteoarthritis.

1.5.2.4  Pectins Hydrocolloids such as pectins are used in occlusive and semiocclusive dressings for wound management. Pectin is a biocompatible and biodegradable natural polymer widely used in food industry, targeted drug delivery, wound healing materials, and tissue engineering (Mishra et al., 2012; Munarin et al., 2012).

1.6  Protein-based biomaterial Proteins are referred to as polypeptides which are composed of up to 20 different amino acid building blocks. Protein biomaterials are unique in that the sequence of the monomers in the polymer chain is predetermined by the template-specific reamer of the polymerization process (Ratner et al., 2013).

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1.6.1   Collagen Collagen is the most abundant protein in the human body and in the skin, and it exists mostly in fibrils. Each collagen molecule in the dermal ECM is a triple-helix structure, consisting of amino acids, mainly glycine, proline, and hydroxyproline. The collagen molecule is assembled into a super-helix procollagen molecule intracellularly and then secreted into the extracellular space (Fleck and Simman, 2010). The parallel alignment of collagen fibers gives a structure with the tensile strength of a light steel wire (Ige et al., 2012) (Fig. 1.3). Collagen is synthesized mainly by fibroblasts and is involved in all phases of the wound healing cascade (Mogosanu and Grumezescu, 2014). Bovine and fish collagens are the most well-known natural biomaterials on the market. The first medical use of collagen in humans was to provide correction of contour deformities (Knapp et al., 1977). Collagen has since been widely used in several forms and applications such as sutures, hemostatic agents, injectable materials, wound dressings, gels for periodontal reconstruction, sponges for hemostasis, and coatings of joints (Hafemann et al., 1999; Ortega et al., 2000; Gingras et al., 2003; Park et al., 2004). Collagen is usually implanted in a sponge form without significant mechanical strength or stiffness. Due to its hydrophilicity, collagen is easily blended with other polymers. Collagen and its degradation products are often used to attract fibroblasts during skin repair and fracture healing (Lee et al., 2003). Collagen-based wound dressings have distinctive practical and economic advantages compared to growth factor and cell-based therapies (Table 1.4). Collagen dressings formulated from bovine, porcine, or avian sources are recommended for the treatment of partial-thickness and full-thickness wounds with minimal-to-moderate exudation, but contraindicated for third-degree skin burns (Ruszczak, 2003). Depending on its processing, collagen can potentially alter cell growth and motility, have inappropriate mechanical properties, or shrink. Cells are able to pull and reorganize collagen fibers, causing scaffolds to lose their shape if not properly stabilized by cross-linking or incorporation of less “vulnerable” materials. Collagen fibers Collagen fibril Type I collagen

α1 collagen protein chain

Triple helix of 2 α1 chains 1 α2 chain

Figure 1.3  Organized fiber bundles constituting collagen. Reprinted with permission from the publisher: Fleck, C.A., Simman, R., 2010. Modern collagen wound dressing: Function and purpose. J. Am. Col. Certif. Wound Spec. 2 (3), 50–54.

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Table 1.4 

Commercial forms of collagen wound dressing (Chattopadhyay and Raines, 2014) Collagen form

Name

Manufacturer

Description

Collagen composite dressing

Promogran®

Systagenix

Fibracol®

Systagenix

Biobrane®

Smith & Nephew

Helitene® Instat®

Integra LifeSciences Ethicon

Avitene® Medifil®

Davol BioCore (Kollagen)

Helistat®

Integra LifeSciences MedChem BioCore (Kollagen)

Collagen-oxidized regenerated cellulose Collagen-alginate wound dressing Artificial skin substitute composed of nylon mesh, silicone, and porcine skin collagen Microfibrillar, absorbable hemostatic agent Microfibrillar collagen hemostat Microfibrillar hemostat Spherically particles of native bovine collagen Absorbable hemostatic sponge

Collagen fiber

Collagen powder Collagen sponge

ActiFoam® SkinTemp®

Hemostatic sponge Native collagen in the nonhydrolyzed form

1.6.2  Gelatin Gelatin is obtained from denatured collagen. Gelatin lacks antigenicity in comparison to its precursor and is biocompatible, biodegradable, and nonimmunogenic. Type A (GA) gelatin is derived from acid-treated material and type B (GB) from alkali-treated material. GA has an isoelectric point (pI) value of 8–9 (a positive charge at neutral pH), whereas GB has a pI value of 4.8–5.4 (a negative charge at neutral pH) (Maxey and Palmer, 1967). Gelatin is widely used as scaffold for tissue engineering and in medicine as an absorbable compressed sponge for hemostasis (Surgifoam®, Ethicon; Gelfoam®, Pfizer); wound dressings; and as an adhesive, absorbent pad for surgical use (Yao et al., 2002; Lee et al., 2003).

1.6.3  Keratin Keratin defines all intermediate filament-forming proteins found in vertebrate epithelia and corneous tissues such as horns, claws, and hooves (Bragulla and Homberger, 2009). The structural integrity and solubility of keratin as well as its natural biocompatibility, controllable biodegradability, and bioactivity make keratin an ideal medical polymer (Ige et al., 2012). Keratin extracted from hair and wool is used as platform technology to make a new family of biomaterials for biomedical applications. Animal-derived keratins seem compatible with human biological systems if carefully extracted (Mueller, 2005). Extracted proteins from human hair formulated in a hydrogel were hemostatic and had

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the ability bind cells (Aboushwareb et al., 2009). Keratin derivatives in wound dressings interact with the proteolytic wound environment of chronic wounds (Mogosanu and Grumezescu, 2014). Keratin can be used for nerve regeneration by activation of Schwann cells (Sierpinski et al., 2008). Moreover, keratin derived from human hair is neuroinductive, and the effect was comparable to autograft in a nerve injury model (Ige et al., 2012). A controlled-release profile was achieved with antibiotics and growth factors incorporated in keratin-based wound dressings (Vasconcelos and Cavaco-Paulo, 2011).

1.6.4   Fibrin Fibrin is a fibrous, nonglobular protein derived from fibrinogen by the action of the serine protease thrombin (Mogosanu and Grumezescu, 2014). Fibrin is used as a natural scaffold for wound healing and as a carrier for cells for transplantation. A fibrin–HA matrix was used for implantation of chondrocytes to symptomatic–chronic cartilage defects (Nehrer et al., 2008). Cardiomyocytes encapsulated in a fibrin hydrogel have been explored for cardiac tissue engineering (Ye et al., 2011). A dressing composed of salmon fibrinogen and thrombin with hemostatic and antiinflammatory properties was evaluated in full-thickness skin lesions in pigs (Rothwell et al., 2009). The pigs treated with the salmon fibrinogen–thrombin bandages showed a smooth recovery course in terms of both tissue healing and the immune response, without adverse effects from the exposure to the fish proteins (Rothwell et al., 2009).

1.6.5  Bovine serum albumin Bovine serum albumin (BSA) or Fraction V is widely used for pharmaceutical (Aramwit et al., 2000; Benko et al., 2015; Lomova et al., 2015) and tissue engineering applications (Kasalkova et al., 2014; Zhang et al., 2015b). BSA is relatively inexpensive since large quantities are readily purified from blood, which is a by-product of the cattle industry. Due to its stability and biochemical inertness, BSA is often included to increase the signals in enzyme-linked immunosorbent, immunoblotting, and immunohistochemical assays. BSA is also used as a nutrient in cell and microbial cultures. BSA fibers, made by electrospinning without the addition of cross-linking agents, are biocompatible and biodegradable and show favorable biomechanical properties (Dror et al., 2008). This biomaterial is therefore attractive for many wound applications (Dror et al., 2008).

1.6.6   Silk fibroin Silk is a natural fibrous protein spun by lepidopteran larvae such as silkworms; spiders; scorpions; mites; and flies (Jin et al., 2004). Silk fibroin is obtained from silk fiber (Fig. 1.4). Fibroin from the most common silkworm, Bombyx mori, is comprised of a heavy chain of 325 kDa and light chain of 25 kDa, with poor water solubility. The structural sequence consists of a crystalline domain (heavy chain) mostly composed of glycine, alanine, serine, and tyrosine amino acid repeats (GAGAGSGAAG[SG(AG)2]8Y) and a short amorphous (light chain) domain of bulkier amino acid side chain of aspartic acid. The amino acid sequence enables the silks to form an

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Fibroin

Sericin

Figure 1.4  Scanning electron image (×1000) of silk fiber consisting of silk fibroin (fibrous protein) and silk sericin (globular protein). Scale = 10 μm.

antiparallel β-pleated sheet secondary structure which gives silk its unique mechanical properties. Fibroin supports adhesion and growth of anchorage-dependent cells such as fibroblasts (Minoura et al., 1995). Fibroin is permeable to oxygen and water vapor, has relatively low thrombogenicity, and elicits only a minimal inflammatory response (Altman et al., 2003; Li et al., 2003; Kanokpanont et al., 2012). The presence of the RGD sequence—l-arginine, glycine, and l-aspartic acid—makes this protein suitable not only for skin regeneration, but also for bone and ligament repair (Sofia et al., 2001; Altman et al., 2003). Spiders can process silk protein into a material that is 16 times stronger and 2–3 times more elastic than nylon (Ige et al., 2012). Silks can also supercontract, especially when immersed into liquids. Silk fibroin is prepared in gels, powders, films, matrices, scaffolds, and fibers for biomedical applications. Coating silk fibroin with waxes such as carnauba wax, shellac wax, or beeswax showed improved mechanical properties compared with the noncoated fibroin fiber (Fig. 1.5). Furthermore, the coated fibroin fiber adhered less to the surface of wounds made in pig skin in vitro compared with petrolatum mesh dressing (Sofra-Tulle®), making dressing changes less painful to the patient and gentler to the wound tissue (Kanokpanont et al., 2012). Moreover, silk fibroin mixed with chitosan, gelatin, alginate, or synthetic polymers such as polyvinyl alcohol or poly(lactide-co-glycolic acid) showed improved physical properties such as tensile strength, porosity, swelling rate, and degradation and improved biological properties such as increased attachment and proliferation of L929 fibroblasts. Also, in vivo experiments indicated increased angiogenesis and improved collagen organization by using these hybrid biomaterials (Gu et al., 2013; Shahverdi et al., 2014; Shan et al., 2015).

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Figure 1.5  Image from scanning electron microscope of silk fibroin woven fabric after sericin removal ((a) 10 kV ×50 and (b) 10 kV ×2000). Scale = 500 mm (a). Scale = 10 µm (b).

1.6.7   Silk sericin Sericin is a degumming silk protein extracted from the silk cocoon. Sericin has several beneficial effects on the stratum corneum of the skin, leading to an improved skin barrier function (Padamwar et al., 2005). Other biological activities of silk sericin include promotion of fibroblast proliferation (Aramwit et al., 2009a,b) and collagen production (Aramwit and Sangcakul, 2007; Aramwit et al., 2010b). An in vitro experiment indicated that sericin at 100 μg/mL or more increased fibroblast repopulation rate of a cell-free polystyrene surface compared with a control under serum-free conditions. The stimulatory effect of sericin was similar to that of epidermal growth factor treatment (Aramwit et al., 2013a). In Fig. 1.6 the beneficial and additional effect of sericin on the healing of split-thickness skin graft donor site wounds in humans is shown (Aramwit et al., 2013a). Sericin in the presence of fibroin, as in native fibers, can activate the immune system (Zaoming et al., 1996). In contrast, pure soluble sericin proteins extracted from native silk fibers did not activate macrophages significantly, indicated by proinflammatory cytokine secretion (Panilaitis et al., 2003; Aramwit et al., 2009a,b). Accordingly, implantation of sericin scaffolds subcutaneously showed no signs of inflammation in standardized ISO 10993-6 test in rats. Furthermore, no excessive inflammatory reaction was observed around the implantation sites. At each time point during the 21-day implantation period, the number of inflammatory cells that infiltrated the silk sericin–releasing wound dressing was comparable to that of a commercial dressing (Bactigras®). Sericin also possesses antiinflammatory activity (Aramwit et al., 2013c). The silk sericin–releasing wound dressing was judged as being nonirritating throughout the implantation period compared to a control in rats (Siritientong et al., 2014). Sericin is water soluble and be can mixed with other polymers into films (Teramoto et al., 2008; Siritientong and Aramwit, 2012), hydrogels (Kundu and Kundu, 2012; Wang et al., 2014), and scaffolds (Aramwit et al., 2010c, 2015). The physical appearances of

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Figure 1.6  Effect of the addition of sericin to an experimental petrolatum dressing containing 1% (w/v) silver sulfadiazine and 1% zinc oxide (control) on the healing of donor sites in burn patients (Aramwit et al., 2013a). Treatments were changed daily. Mean ± SD. n = number of wounds. ***p < 0.001.

sericin film cross-linked with genipin and scaffold composed of sericin, polyvinyl alcohol, and glycerin fabricated using a freeze-drying technique are shown in Fig. 1.7. The mechanical properties of sericin are improved when combined with other biomaterials such as poly(γ-glutamic acid) (Shi et al., 2015), polyvinyl alcohol (Aramwit et al., 2015), CMC (Nayak and Kundu, 2014), or gelatin (Hasatsri et al., 2015). Sericin scaffolds fabricated with different polymers and cross-linkers promote cell proliferation and differentiation. Moreover, they accelerate wound healing in vivo (Aramwit, 2011,2012; Kanokpanont et al., 2012; Siritienthong et al., 2012; Aramwit et al., 2013b). Full-thickness skin wounds in rats treated with sericin/polyvinyl alcohol scaffold showed faster wound area reduction (p < 0.05) compared to the wounds treated with the sericin-free scaffold (Siritienthong et al., 2012). In a clinical study on split-thickness skin graft donor site wounds, the sericin scaffold reduced the time to healing and the pain significantly compared to Bactigras® (Siritientong et al., 2014). Hyperpigmentation is common sequelae of inflammatory conditions that seems to be more common and severe in dark-skinned patients. The treatment results with hydroquinone or retinoic acid are mediocre. Wound treatment with sericin seems to reduce the postoperative hyperpigmentation of scars (Siritientong et al., 2014), perhaps due to the antityrosinase activity of sericin (Aramwit et al., 2010b).

1.7  Nanofiber-based biomaterial Nanofibrous membranes are highly soft materials with high surface-to-volume ratios, and they are excellent carriers for therapeutics such as antimicrobial agents and wound healing enhancers (Zhong et al., 2010b). In nature, very few biomaterials

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Figure 1.7  Physical appearance of sericin film cross-linked with genipin (left; the dark color of the film is due to genipin) and sericin scaffold–stabilized polyvinyl alcohol and glycerin at weight ratio of 3:2:1 (right). Adapted from Aramwit, P., Palapinyo, S., Srichana, T., Chottanapund, S., Muangman, P., 2013a. Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds. Arch. Dermatol. Res. 305, 585–594.

are presented in the form of fibers. One exception is cellulose which is a natural fiber material. Other carbohydrate and protein materials can be formed as nanofibers by using various techniques such as self-assembly, phase separation, and electrospinning (Vasita and Katti, 2006). Electrospinning is a technique for producing ultrafine fibers as a result of charging and ejecting a biomaterial melt or solution through a spinneret under a high-voltage electric field (up to 30 kV) and solidifying it to form a filament. This technique can be used for natural biomaterials such as collagen, silk fibroin, and chitosan and for the synthetic biomaterials (Zhong et al., 2010b) polyvinyl alcohol and PLA. A nonwoven silk fibroin nanofiber coated with type I collagen by electrospinning for skin tissue engineering has been developed (Min et al., 2004). The material promoted keratinocyte–fibroblast adhesion and spreading due to its high porosity and high surface-to-volume ratio (Min et al., 2004). Other examples are electrospun polyurethane nanofiber membranes which provide optimal oxygen permeability and preventing dehydration of the wound (Khil et al., 2003). Moreover, the ultrafine porosity of the polyurethane nanofiber membranes was an effective barrier against microorganisms.

1.8  Marine biomaterial Marine biomaterials for tissue engineering and wound healing are normally sulfated polysaccharides which have diverse functions in the tissues. They bind proteins at several levels of specificity and are mainly involved in the development, cell proliferation, cell adhesion, cell signaling, and cell–matrix interactions (Senni et al., 2011). Marine

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polysaccharides present an enormous variety of structures. Sulfated polysaccharides, possessing GAG-like biological properties, can be found either in marine eukaryotes or in marine prokaryotes.

1.8.1  Sulfated polysaccharides from red algae Carrageenans are sulfated polysaccharides that occur as matrix material in several species of red seaweeds. The sulfate content largely determines the biological activities of carrageenans (Opoku et al., 2006). κ-Carrageenan possesses antioxidant, antitumor, and immunomodulation activities (Zhou et al., 2004; Yuan et al., 2006). Anticoagulant and growth factor activities have also been reported for carrageenan (Hoffman, 1993; Farias et al., 2000). Nevertheless, carrageenan biocompatibility has been questioned in the literature, with examples of inflammatory responses being presented (Morris, 2003; Aramwit et al., 2013c). It should be emphasized that food-grade carrageenan and degraded carrageenan (low molecular weight) have completely different toxicological properties (Cicala et al., 2007). For tissue engineering and wound healing, carrageenan has been considered for growth factor/ drug delivery systems (Santo et al., 2009), immobilization of enzymes (Desai et al., 2004), and encapsulation of cells for in vivo delivery (Rocha et al., 2011; Popa et al., 2012).

1.8.2  Sulfated polysaccharides from green algae Sulfated polysaccharides found in green algae are more complex and diverse chemistries compared to sulfated polysaccharides found in marine invertebrates (Pomin and Mourao, 2008). These polysaccharides are antioxidative, scavenging radical oxygen species, chelating metals (Costa et al., 2010), antiproliferative, immunostimulating, and antitumorgenic (Kim et al. 2011). Nanofibers (Toskas et al., 2011), membranes (Alves et al., 2012), 3D porous structures (Alves et al., 2013), and hydrogels (Morelli and Chiellini, 2010) have been developed from native, modified, or processed forms of these polysaccharides that may be used for drug delivery, wound dressings, and bone tissue engineering (Morelli and Chiellini, 2010; Alves et al., 2012, 2013).

1.8.3  Sulfated polysaccharides from brown algae Brown macroalgae are rich in polysaccharides such as alginic acids (alginate) or laminarins (laminarans) and sulfated fucans which are potential therapeutic agents. Fucoidan is found in the cell wall of these algae, amounting to 5–20% of the algae dry weight (Vera et al., 2011). For tissue engineering and wound healing application, fucoidan is normally combined with different polymers such as chitosan, alginate, or polycaprolactone processed into nanofibers, films, scaffolds, and hydrogels (Sezer et al., 2007; Murakami et al., 2010). Fucoidan-chitosan hydrogel has been applied as burn injury healing accelerator in rabbits (Sezer et al., 2008). Hydrogel sheets composed of alginate, chitosan, and fucoidan stimulated wound healing in rats (Murakami

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et al., 2010). These materials showed advantages over chitosan due to the hydrogel-forming properties and anticoagulant activity of fucoidan (Silva et al., 2012).

1.9  Biomaterials with antimicrobial activity Wound infection is a manifestation of disturbed host–bacteria equilibrium in a traumatized tissue environment in favor of bacterial proliferation. A wound infection can elicit a systemic response such as sepsis, but also inhibit any process of the wound healing cascade (Robson 1997; Dai et al., 2011). Antimicrobial biomaterials used for fabrication are especially interesting.

1.9.1   Honey The antimicrobial activity of honey is well established, and many modern wound care products contain medical-grade honey. It has been documented that honey is bactericidal against at least 70 Gram-positive and Gram-negative bacterial strains and some yeasts (Cooper, 2008). Like sugar pastes, honey is hypertonic and inhibits bacterial growth through osmosis (Cooper, 2008). Therefore honey is often used to inhibit the growth of bacterial strains resistant to conventional antibiotics. Honey also facilitates autolytic debridement and maintains a moist wound environment. Despite these beneficial effects, research trends are controversial with respect to the overall clinical efficacy of honey (Henriques et al., 2006; Molan, 2006).

1.9.2   Iodine Iodine, a natural halogen, is an antiseptic and targets a broad spectrum of bacteria and other pathogens such as fungi, viruses, protozoa, and prions through a nonspecific action (Cooper, 2007). The use of iodine has declined due to the increase in resistant bacterial strains and the cytotoxicity of elemental iodine against fibroblasts, keratinocytes, and leukocytes, which may impede wound healing. Modern preparations of iodine were therefore developed to complex elemental iodine to a surfactant to improve solubility and reduce the cytotoxic effects (Daunton et al., 2012). The use of iodophors in wound dressings ensures release of lower concentrations of free iodine into the wound (Jones and San Miguel, 2006). The most widely used formulations are povidone-iodine and cadexomer-iodine. Even these formulations at concentrations as low as 1% are cytotoxic to granulocytes and monocytes in vitro (Jones and San Miguel, 2006). Systemic iodine toxicity has been reported after the use povidone-iodine dressings containing 7.5% iodine on large wounds (Jones and San Miguel, 2006). The cadexomer-iodine formulation seems to be effective in controlling the bacterial burden and is also able to accelerate epithelialization through up-regulation of cytokines and growth factors (Lamme et al., 1998; Ohtani et al., 2007). In addition, cadexomer-iodine may improve the healing of chronic wounds by inhibiting excessive protease activities (Eming et al., 2006).

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1.9.3  Silver Silver dressings are used in a wide range of infected wounds, although their potential cytotoxicity remains an issue (Wei et al., 2010; Zou et al., 2013). Ionic, metallic, and nanocrystalline forms of silver have been used as foams, alginates, hydrofibers, and hydrocolloids. The amount of bioavailable free silver varies, which impacts the effectiveness of the dressings on wound healing. Silver ions act upon bacteria by binding and disrupting proteins and nucleic acids through interaction with their negatively charged groups such as thiols, carboxylates, phosphates, hydroxyls, imidazoles, indoles, and amines as well as by stimulating the generation of reactive oxygen species (Kim et al., 2012). As a result, cellular changes rapidly occur through several mechanisms, resulting in loss of viability (Cooper, 2004). Silver nanoparticles penetrated into mitochondria and nuclei and interrupted ATP synthesis and damaged DNA of human glioblastoma cells and lung fibroblasts in vitro (Asharani et al., 2009). Other studies indicated that silver nanoparticles were cytotoxic to keratinocytes in vitro (Sibbald et al., 2011; Zanette et al., 2011).

1.9.4  Chitosan Many factors present in the chitosan molecule or its environment can influence the antimicrobial properties such as molecular weight, ionic strength, pH of the dissolving medium, and the physical state of the chitosan itself (Dai et al., 2011). The exact mechanisms of the antimicrobial actions of chitosan are still uncertain, but it has been proposed that interaction between positively charged chitosan molecules and negatively charged microbial cell membranes leads to the disruption of microbial membrane, and subsequently the leakage of protein as well as other intracellular constituents (Rabea et al., 2003; Raafat et al., 2008; Kong et al., 2010). Use of fluorescent probes and field emission scanning electron microscopy indicated that chitosan-arginine increases membrane permeability, which could partly explain its antibacterial activity (Tang et al., 2010). Chitosan is essentially water insoluble at physiological pH, but the solubility is increased when functionalized with arginine. Furthermore, at low concentrations (<0.2 mg/mL), the polycationic chitosan binds to the negatively charged bacterial surface causing agglutination, whereas at higher concentrations, the larger number of positive charges have imparted a net positive charge to the bacterial surfaces to keep them in suspension (Rabea et al., 2003). Many studies showed that chitosan prevents fatal systemic sepsis by controlling the growth of Pseudomonas aeruginosa and Pseudomonas mirabilis in wounds (Dai et al., 2009; Dutta et al., 2012). A chitosan acetate dressing was even superior to nanocrystalline silver with respect to survival from P. aerugnosa-infected burn wounds (Dai et al., 2009).

1.10  Biomaterials used for corneal wound healing Skin and cornea share a similar tissue structure: dermis and stroma are connective tissues, and epidermis and cornea are stratified epithelia (Parenteau-Bareil et al., 2010). The cornea is the most vital refractive medium in the anterior part of the eye, and it

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is responsible for two-thirds of the total ocular refractive power. Disease affecting the cornea is a common cause of blindness worldwide. To date, the amniotic membrane is the most widely used clinical method for cornea regeneration (Tsai et al., 2015). Donor-dependent differences in the amniotic membrane may result in variable clinical outcomes. Thus other biomaterials are currently under investigation for corneal regeneration.

1.10.1  Collagen/gelatin Collagen is the most abundant protein in the human cornea (Michelacci, 2003). Advances in collagen-based corneal scaffolds also include recombinant human collagen (Liu et al., 2006; Lagali et al., 2008), the secretion of collagen by the fibroblasts themselves (self-assembled fibroblasts sheets) (Carrier et al., 2008), and surface modification to reduce endothelialization (Rafat et al., 2009). In the last decade, collagen scaffolds have been intensively studied for the delivery of limbal epithelial stem cells to damaged cornea (Schwab, 1999; Grueterich et al., 2003). Collagen hydrogels are biocompatible, biodegradable, and maintain the proliferation and differentiation of limbal epithelial cells. In clinical studies corneal reepithelialization occurred in all patients who had significant vision loss after treatment with a cross-linked collagen hydrogel (Fagerholm et al., 2010, 2014). Gelatin hydrogels have been used as cell carriers, including corneal endothelial and stromal cells, and for sustained ocular drug release for corneal regeneration (Hori et al., 2007; Watanabe et al., 2011). An animal study showed that transplantation of fibroblast precursors into the corneal stroma from a gelatin hydrogel promoted wound healing of the cornea (Mimura et al., 2008).

1.10.2  Fibrin Fibrin hydrogels increase the survival rate of limbal stem cells, while maintaining their phenotype during culturing (Meyer-Blazejewska et al., 2010; Rama et al., 2010). Moreover, fibrin hydrogels are degraded within 24 h after transplantation, which is ideal for a cell carrier biomaterial (Meyer-Blazejewska et al., 2010). In a clinical study, patients with corneal damage regained useful vision after treatment with autologous limbal stem cells that had been cultured on autologous fibrin hydrogel (Rama et al., 2010). Mesenchymal stem cells are also widely investigated for their use in corneal regeneration. Mesenchymal stem cells can differentiate into corneal epithelial-like cells in vivo and ex vivo (Tsai et al., 2015). The studies showed that injured cornea in rabbits could be successfully reconstructed by delivery of mesenchymal stem cells that had been cultured on fibrin hydrogels (Ye et al., 2006; Gu et al., 2009).

1.10.3  Alginate There are few studies on alginates in ophthalmology (Lee and Mooney, 2012; Pawar and Edgar, 2012). Nonetheless, these studies indicate that alginate-based hydrogels are promising carriers for limbal epithelial cells and thus for corneal regeneration applications (Liang et al., 2011; Wright et al., 2012).

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1.10.4  Chitosan Chitosan-based biomaterials have been investigated for ocular drug and cell delivery (Cao et al., 2007; Yeh et al., 2009). A chitosan membrane promoted wound healing and decreased scar tissue formation in a rabbit corneal alkali burn model (Du et al., 2008). Chitosan-based hydrogels combined with induced pluripotent stem cells were reported effective in the treatment of surgical abrasion–injured corneas in rats (Chien et al., 2012).

1.11  Trends of biomaterials used for wound healing The search for the ideal wound dressing is ongoing. With the application of modern biotechnologies and tissue engineering skills combined with conventional materials, advanced wound treatments are steadily being improved.

1.11.1  Extracellular matrix-derived biomaterials Biologics describe ECM-based products of human or animal sources (Mathur et al., 1997; Badylak et al., 2002; Badylak, 2002). The rationale behind the use of these biomaterials/bioscaffolds is replicating the biological and mechanical function of the native ECMs that ascertain optimal conditions not only for repair but also for regeneration of new tissue (Bellows et al., 2007). Different mechanisms have been proposed, including promotion of angiogenesis, recruitment of circulating progenitor cells, rapid scaffold degradation and generation of active peptides, and antibacterial activity (Badylak, 2002). One challenge when producing these biomaterials is to completely remove cells and antigens of the native materials without altering their 3D structure and their biological and mechanical properties. Human acellular dermal matrices derived from cadavers include Alloderm® (LifeCell, Branchburg, NJ, USA) and GraftJacket® (KCI, San Antonio, TX, USA). These allografts are thought to support the body’s own healing capacity. Small intestine submucosa (SIS) is derived from the thin, translucent tunica submucosa layer of the small intestine of pigs which remains after removing the mucosal and muscular layers. SIS consists primarily of a collagen-based extracellular matrix which provides strength, structural support, and stability and signals to the constantly regenerating mucosal cell layer (Ko et al., 2006; Chang et al., 2013). SIS also contains many growth factors. In vitro studies indicate that SIS provides an environment that ensures fibroblast and keratinocyte attachment, proliferation, and migration (Voytik-Harbin et al., 1998). Commercially, sterile single-use monolayer and trilayer SIS are available (Smith & Nephew, London, UK). The trilayer product is stronger than the monolayer and therefore supports more suture tension. Using tissue engineering techniques, many physical and chemical properties such as the composition and structure of the matrix, molecular composition, flexibility, thickness, tensile strength, elasticity, degradation rate, and the remodeling behavior can be recapitulated to the need of the specific repair site (Gobin et al., 2006). Several

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natural biomaterials, such as silk protein, chitosan, and collagen, are promising starting materials in engineered products with reparative and regenerative capacity. One example is Biobrane® (Smith & Nephew), which is a biocomposite dressing composed of a silicone–nylon matrix in which collagenous peptides from porcine skin have been covalently bonded.

1.12  Limitations of biomaterials for wound healing applications The main limitation of synthetic biomaterials is biocompatibility with human tissues which may cause problems after their use for extended times. Moreover, the impurity from precursors or byproducts may affect the physical and biological properties of these biomaterials. Although biocompatibility is not a significant concern with natural biomaterials, there are other limitations associated with their use: 1. Productivity: Due to the natural sources of these biomaterials which are difficult to control, the amount of some natural biomaterials may not be sufficient for practical use. 2. Consistency: The origin of natural materials may affect their properties. The same animal species found in different areas may produce biomaterials with slightly different physical and biological activities. Moreover, the extraction methods need to be verified to provide good-quality materials. 3. Degradation: Most natural biomaterials are susceptible for degradation, especially after extraction and exposure to heat and light. Some natural products are recommended to be used immediately after extraction to avoid the nonuniformity. 4. Contamination: Some natural biomaterials such as proteins are excellent growth media for microorganisms. Sterilization may have adverse effects on the structure or properties of the materials.

Despite these limitations, natural biomaterials have advantages over synthetic biomaterials via their versatility, biocompatibility, sustainability, green chemistry issues, and various biological properties from single material. These features may explain the growing interest of natural biomaterials in all biomedical areas.

1.13   Conclusions According to the variation in the rate of production of wound exudate and the appearance of the wound bed, no single wound dressing, either from synthetic or natural biomaterials, is beneficial for all wound types. The main challenge is to develop novel wound healing drug delivery or cell delivery formulations that have the capacity to positively influence the majority of wounds. Novel biomaterials and other active ingredients such as growth factors, pharmaceuticals, or cells can stimulate the healing cascade. These materials combined with tissue engineering techniques provide a better chance for optimal treatment and management resulting in positive clinical outcomes.

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References Aboushwareb, T., Eberli, D., et al., 2009. A keratin biomaterial gel hemostat derived from human hair: evaluation in a rabbit model of lethal liver injury. J. Biomed. Mater. Res. B Appl. Biomater. 90 (1), 45–54. Agrawal, C.M., 1998. Reconstructing the human body using biomaterials. JOM 50 (1), 31–35. Ågren, M.S., 1998. An amorphous hydrogel enhances epithelialisation of wounds. Acta Derm. Venereol. 78 (2), 119–122. Ågren, M.S., Ostenfeld, U., et al., 2006. A randomized, double-blind, placebo-controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision. Wound Repair Regen. 14 (5), 526–535. Altman, G.H., Diaz, F., et al., 2003. Silk-based biomaterials. Biomaterials 24 (3), 401–416. Alves, A., Pinho, E.D., et al., 2012. Processing ulvan into 2D structures: cross-linked ulvan membranes as new biomaterials for drug delivery applications. Int. J. Pharm. 426 (1–2), 76–81. Alves, A., Sousa, R.A., et al., 2013. Processing of degradable ulvan 3D porous structures for biomedical applications. J. Biomed. Mater. Res. A 101 (4), 998–1006. Anderson, J.M., Hiltner, A., et al., 1998. Recent advances in biomedical polyurethane biostability and biodegradation. Polym. Int. 46 (3), 163–171. Aramwit, P., 2011. Method for preparing silk sericin-PVA scaffold using Genipin as crosslinking agent. I. A. N. PCT/TH2011/000013. Aramwit, P., 2012. Method for preparing porous silk sericin scaffold by cross-linking process and products from the same. T. p. g. n. 9423. Aramwit, P., Bang, N., 2014. The characteristics of bacterial nanocellulose gel releasing silk sericin for facial treatment. BMC Biotechnol. 14, 104. Aramwit, P., Damrongsakkul, S., et al., 2010a. Properties and antityrosinase activity of sericin from various extraction methods. Biotechnol. Appl. Biochem. 55 (2), 91–98. Aramwit, P., Kanokpanont, S., et al., 2009a. The effect of sericin with variable amino-acid content from different silk strains on the production of collagen and nitric oxide. J. Biomater. Sci. Polym. Ed. 20 (9), 1295–1306. Aramwit, P., Kanokpanont, S., et al., 2009b. Monitoring of inflammatory mediators induced by silk sericin. J. Biosci. Bioeng. 107 (5), 556–561. Aramwit, P., Kanokpanont, S., et al., 2010b. The effect of sericin from various extraction methods on cell viability and collagen production. Int. J. Mol. Sci. 11 (5), 2200–2211. Aramwit, P., Palapinyo, S., et al., 2013a. Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds. Arch. Dermatol. Res. 305 (7), 585–594. Aramwit, P., Ratanavaraporn, J., et al., 2015. A green salt-leaching technique to produce sericin/ PVA/glycerin scaffolds with distinguished characteristics for wound-dressing applications. J. Biomed. Mater. Res. B Appl. Biomater. 103 (4), 915–924. Aramwit, P., Sangcakul, A., 2007. The effects of sericin cream on wound healing in rats. Biosci. Biotechnol. Biochem. 71 (10), 2473–2477. Aramwit, P., Siritienthong, T., et al., 2013b. Accelerated healing of full-thickness wounds by genipin-crosslinked silk sericin/PVA scaffolds. Cells Tissues Organs 197 (3), 224–238. Aramwit, P., Siritientong, T., et al., 2010c. Formulation and characterization of silk sericin-PVA scaffold crosslinked with genipin. Int. J. Biol. Macromol. 47 (5), 668–675. Aramwit, P., Towiwat, P., et al., 2013c. Anti-inflammatory potential of silk sericin. Nat. Prod. Commun. 8 (4), 501–504. Aramwit, P., Yu, B.G., et al., 2000. The effect of serum albumin on the aggregation state and toxicity of amphotericin B. J. Pharm. Sci. 89 (12), 1589–1593. Asharani, P.V., Hande, M.P., et al., 2009. Anti-proliferative activity of silver nanoparticles. BMC Cell Biol. 10, 65.

Introduction to biomaterials for wound healing

29

Atala, A., Mooney, D., 1997. Synthetic Biodegradable Polymer Scaffolds. Birkhauser BioSciences, New York, USA. Badylak, S., Kokini, K., et al., 2002. Morphologic study of small intestinal submucosa as a body wall repair device. J. Surg. Res. 103 (2), 190–202. Badylak, S.F., 2002. The extracellular matrix as a scaffold for tissue reconstruction. Semin. Cell Dev. Biol. 13 (5), 377–383. Bajpai, A.K., Giri, A., 2003. Water sorption behaviour of highly swelling (carboxy methylcellulose-g-polyacrylamide) hydrogels and release of potassium nitrate as agrochemical. Carbohydr. Polym. 53 (3), 271–279. Bellows, C.F., Albo, D., et al., 2007. Abdominal wall repair using human acellular dermis. Am. J. Surg. 194 (2), 192–198. Benko, M., Varga, N., et al., 2015. Bovine serum albumin-sodium alkyl sulfates bioconjugates as drug delivery systems. Colloids Surf. B Biointerfaces 130, 126–132. Beran, M., Urban, M., et al., 2007. Applications of Mushroom Chitosans in Medical Biomaterials. From: http://www.vupp.cz/czvupp/publik/07poster/MBposter4-2007-1.pdf. Biliaderis, C., 1992. Structure and phase transition of starch in food systems. Food Technol. 46 (6), 98–109. Bradford, C., Freeman, R., et al., 2009. In vitro study of sustained antimicrobial activity of a new silver alginate dressing. J. Am. Col. Certif. Wound Spec. 1 (4), 117–120. Bragulla, H.H., Homberger, D.G., 2009. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J. Anat. 214 (4), 516–559. Brochu, A.B., Craig, S.L., et al., 2011. Self-healing biomaterials. J. Biomed. Mater. Res. A 96 (2), 492–506. Brown-Etris, M., Cutshall, W., et al., 2002. A new biomaterial derived from small intestine submucosa and developed into a wound matrix device. Wounds 14 (4), 150–166. Cao, Y., Zhang, C., et al., 2007. Poly(N-isopropylacrylamide)-chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. J. Control. Release 120 (3), 186–194. Carrier, P., Deschambeault, A., et al., 2008. Characterization of wound reepithelialization using a new human tissue-engineered corneal wound healing model. Invest. Ophthalmol. Vis. Sci. 49 (4), 1376–1385. Chang, J., DeLillo Jr., N., et al., 2013. Review of small intestine submucosa extracellular matrix technology in multiple difficult-to-treat wound types. Wounds 25 (5), 113–120. Chattopadhyay, S., Raines, R.T., 2014. Review collagen-based biomaterials for wound healing. Biopolymers 101 (8), 821–833. Chien, Y., Liao, Y.W., et al., 2012. Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel. Biomaterials 33 (32), 8003–8016. Cho, Y.W., Cho, Y.N., et al., 1999. Water-soluble chitin as a wound healing accelerator. Biomaterials 20 (22), 2139–2145. Cicala, C., Morello, S., et al., 2007. Haemostatic imbalance following carrageenan-induced rat paw oedema. Eur. J. Pharmacol. 577 (1–3), 156–161. Cooper, R., 2004. A Review of the Evidence of the Use of Topical Antimicrobial Agents in Wound Care. From: http://www.worldwidewounds.com/2004/february/Cooper/ Topical-Antimicrobial-Agents.html. Cooper, R., 2008. Using honey to inhibit wound pathogens. Nurs. Times 104 (3), 46 48–49. Cooper, R.A., 2007. Iodine revisited. Int. Wound J. 4 (2), 124–137. Costa, L.S., Fidelis, G.P., et al., 2010. Biological activities of sulfated polysaccharides from tropical seaweeds. Biomed. Pharmacother. 64 (1), 21–28. Czaja, W.K., Young, D.J., et al., 2007. The future prospects of microbial cellulose in biomedical applications. Biomacromolecules 8 (1), 1–12.

30

Wound Healing Biomaterials

Dai, T., Tanaka, M., et al., 2011. Chitosan preparations for wounds and burns: antimicrobial and wound-healing effects. Expert Rev. Anti Infect. Ther. 9 (7), 857–879. Dai, T., Tegos, G.P., et al., 2009. Chitosan acetate bandage as a topical antimicrobial dressing for infected burns. Antimicrob. Agents Chemother. 53 (2), 393–400. Daunton, C., Kothari, S., et al., 2012. A history of materials and practices for wound management. Wound Pract. Res. 20 (4), 174–186. Davis, J., 2003. Overview of biomaterials and their use in medical devices. In: Davis, J. (Ed.), Handbook of Materials for Medical Devices. Knovel, Pensylvania, USA. Desai, P.D., Dave, A.M., et al., 2004. Entrapment of lipase into K-carrageenan beads and its use in hydrolysis of olive oil in biphasic system. J. Mol. Catal. B Enzym. 31 (4–6), 143–150. Dror, Y., Ziv, T., et al., 2008. Nanofibers made of globular proteins. Biomacromolecules 9 (10), 2749–2754. Du, L.Q., Wu, X.Y., et al., 2008. Effect of different biomedical membranes on alkali-burned cornea. Ophthalmic Res. 40 (6), 282–290. Dutta, J., Tripathi, S., et al., 2012. Progress in antimicrobial activities of chitin, chitosan and its oligosaccharides: a systematic study needs for food applications. Food Sci. Technol. Int. 18 (1), 3–34. Eming, S.A., Smola-Hess, S., et al., 2006. A novel property of povidon-iodine: inhibition of excessive protease levels in chronic non-healing wounds. J. Invest. Dermatol. 126 (12), 2731–2733. Fagerholm, P., Lagali, N.S., et al., 2010. A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study. Sci. Transl. Med. 2 (46), 46ra61. Fagerholm, P., Lagali, N.S., et al., 2014. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials 35 (8), 2420–2427. Farias, W.R., Valente, A.P., et al., 2000. Structure and anticoagulant activity of sulfated galactans. Isolation of a unique sulfated galactan from the red algae Botryocladia occidentalis and comparison of its anticoagulant action with that of sulfated galactans from invertebrates. J. Biol. Chem. 275 (38), 29299–29307. Fleck, C.A., Simman, R., 2010. Modern collagen wound dressings: function and purpose. J. Am. Col. Certif. Wound Spec. 2 (3), 50–54. Freyman, T.M., Yannas, I.V., et al., 2001. Cellular materials as porous scaffolds for tissue engineering. Prog. Mater. Sci. 46 (3–4), 273–282. Gingras, M., Paradis, I., et al., 2003. Nerve regeneration in a collagen-chitosan tissue-engineered skin transplanted on nude mice. Biomaterials 24 (9), 1653–1661. Gobin, A.S., Butler, C.E., et al., 2006. Repair and regeneration of the abdominal wall musculofascial defect using silk fibroin-chitosan blend. Tissue Eng. 12 (12), 3383–3394. Gobin, A.S., West, J.L., 2003. Effects of epidermal growth factor on fibroblast migration through biomimetic hydrogels. Biotechnol. Prog. 19 (6), 1781–1785. Granick, M., Boykin, J., et al., 2006. Toward a common language: surgical wound bed preparation and debridement. Wound Repair Regen. 14 (Suppl. 1), S1–10. Grueterich, M., Espana, E.M., et al., 2003. Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv. Ophthalmol. 48 (6), 631–646. Gu, S., Xing, C., et al., 2009. Differentiation of rabbit bone marrow mesenchymal stem cells into corneal epithelial cells in vivo and ex vivo. Mol. Vis. 15, 99–107. Gu, Z., Xie, H., et al., 2013. Preparation of chitosan/silk fibroin blending membrane fixed with alginate dialdehyde for wound dressing. Int. J. Biol. Macromol. 58, 121–126. Guerra, L., Dellambra, E., et al., 2009. Tissue engineering for damaged surface and lining epithelia: stem cells, current clinical applications, and available engineered tissues. Tissue Eng. Part B Rev. 15 (2), 91–112.

Introduction to biomaterials for wound healing

31

Hafemann, B., Ensslen, S., et al., 1999. Use of a collagen/elastin-membrane for the tissue engineering of dermis. Burns 25 (5), 373–384. Han, S., 2005. Topical formulations of water-soluble chitin as a wound healing assistant. Fibers and Polym. 6 (3), 219–223. Hasatsri, S., Aungsapat, A., et al., 2015. Randomized clinical trial of the innovative bilayered wound dressing made of silk and gelatin: safety and efficacy tests using a split-thickness skin graft model. Evid. Based Complement Alternat. Med. 2015:Article ID 206871. Heness, G., Ben-Nissan, B., 2004. Innovative bioceramics. Mater. Forum 27, 104–114. Henriques, A., Jackson, S., et al., 2006. Free radical production and quenching in honeys with wound healing potential. J. Antimicrob. Chemother. 58 (4), 773–777. Higgins, S.P., Solan, A.K., et al., 2003. Effects of polyglycolic acid on porcine smooth muscle cell growth and differentiation. J. Biomed. Mater. Res. Part A 67A (1), 295–302. Hirano, S., Midorikawa, T., 1998. Novel method for the preparation of N-acylchitosan fiber and N-acylchitosan-cellulose fiber. Biomaterials 19 (1–3), 293–297. Hoffman, R., 1993. Carrageenans inhibit growth-factor binding. Biochem. J. 289 (Pt 2), 331–334. Hori, K., Sotozono, C., et al., 2007. Controlled-release of epidermal growth factor from cationized gelatin hydrogel enhances corneal epithelial wound healing. J. Control. Release 118 (2), 169–176. Huang, M., Yang, M., 2008. Evaluation of glucan/poly(vinyl alcohol) blend wound dressing using rat models. Int. J. Pharm. 346 (1–2), 38–46. Ige, O.O., Umoru, L.E., et al., 2012. Natural products: a minefield of biomaterials. ISRN Mater. Sci. 2012, 20. Jansson, E., Tengvall, P., 2001. In vitro preparation and ellipsometric characterization of thin blood plasma clot films on silicon. Biomaterials 22 (13), 1803–1808. Jin, H.J., Park, J., et al., 2004. Biomaterial films of Bombyx mori silk fibroin with poly(ethylene oxide). Biomacromolecules 5 (3), 711–717. Jones, A.M., San Miguel, L., 2006. Are modern wound dressings a clinical and cost-effective alternative to the use of gauze? J. Wound Care 15 (2), 65–69. Kanokpanont, S., Damrongsakkul, S., et al., 2012. An innovative bi-layered wound dressing made of silk and gelatin for accelerated wound healing. Int. J. Pharm. 436 (1–2), 141–153. Kasalkova, N.S., Slepicka, P., et al., 2014. Grafting of bovine serum albumin proteins on plasma-modified polymers for potential application in tissue engineering. Nanoscale Res. Lett. 9 (1), 161. Kasuya, A., Tokura, Y., 2014. Attempts to accelerate wound healing. J. Dermatol. Sci. 76 (3), 169–172. Kearney, J.N., 2001. Clinical evaluation of skin substitutes. Burns 27 (5), 545–551. Kennedy, J., Knill, C., et al., 2011. Natural polymers for healing wounds. In: Kennedy, J., Philips, G., Williams, P., Hatakeyama, H. (Eds.), Recent Advances in Environmentally Compatible Polymers. Woodhead Publishing, Cambridge, England. Khil, M.S., Cha, D.I., et al., 2003. Electrospun nanofibrous polyurethane membrane as wound dressing. J. Biomed. Mater. Res. B Appl. Biomater. 67 (2), 675–679. Khor, E., Lim, L.Y., 2003. Implantable applications of chitin and chitosan. Biomaterials 24 (13), 2339–2349. Kim, J.K., Cho, M.L., et al., 2011. In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera. Int. J. Biol. Macromol. 49 (5), 1051–1058. Kim, T.H., Kim, M., et al., 2012. Size-dependent cellular toxicity of silver nanoparticles. J. Biomed. Mater. Res. A 100 (4), 1033–1043. Kindt, T., Goldsby, R., et al., 2007. Kuby Immunology. Freemand and Company, New York, USA.

32

Wound Healing Biomaterials

Knapp, T.R., Kaplan, E.N., et al., 1977. Injectable collagen for soft tissue augmentation. Plast. Reconstr. Surg. 60 (3), 398–405. Ko, R., Kazacos, E.A., et al., 2006. Tensile strength comparison of small intestinal submucosa body wall repair. J. Surg. Res. 135 (1), 9–17. Kong, M., Chen, X.G., et al., 2010. Antimicrobial properties of chitosan and mode of action: a state of the art review. Int. J. Food Microbiol. 144 (1), 51–63. Kundu, B., Kundu, S.C., 2012. Silk sericin/polyacrylamide in situ forming hydrogels for dermal reconstruction. Biomaterials 33 (30), 7456–7467. Kurpinski, K.T., Stephenson, J.T., et al., 2010. The effect of fiber alignment and heparin coating on cell infiltration into nanofibrous PLLA scaffolds. Biomaterials 31 (13), 3536–3542. Lagali, N., Griffith, M., et al., 2008. Innervation of tissue-engineered recombinant human collagen-based corneal substitutes: a comparative in vivo confocal microscopy study. Invest. Ophthalmol. Vis. Sci. 49 (9), 3895–3902. Lamme, E.N., Gustafsson, T.O., et al., 1998. Cadexomer-iodine ointment shows stimulation of epidermal regeneration in experimental full-thickness wounds. Arch. Dermatol. Res. 290 (1–2), 18–24. Lee, J.H., Lim, S.J., et al., 2010. Wound healing evaluation of sodium fucidate-loaded polyvinylalcohol/sodium carboxymethylcellulose-based wound dressing. Arch. Pharm. Res. 33 (7), 1083–1089. Lee, J.J., Worthington, P., 1999. Reconstruction of the temporomandibular joint using calvarial bone after a failed Teflon-Proplast implant. J. Oral. Maxillofac. Surg. 57 (4), 457–461. Lee, K.Y., Mooney, D.J., 2012. Alginate: properties and biomedical applications. Prog. Polym. Sci. 37 (1), 106–126. Lee, S., Jeon, H., et al., 2003. Artificial dermis composed of gelatin, hyaluronic acid and (1→3),(1→6)-β-glucan. Macromol. Res. 11 (5), 368–374. Lehtovaara, B.C., Gu, F.X., 2011. Pharmacological, structural, and drug delivery properties and applications of 1,3-beta-glucans. J. Agric. Food Chem. 59 (13), 6813–6828. Li, M., Ogiso, M., et al., 2003. Enzymatic degradation behavior of porous silk fibroin sheets. Biomaterials 24 (2), 357–365. Liang, Y., Liu, W., et al., 2011. An in situ formed biodegradable hydrogel for reconstruction of the corneal endothelium. Colloids Surf. B Biointerfaces 82 (1), 1–7. Liao, F., Chen, Y., et al., 2010. A novel bioactive three-dimensional beta-tricalcium phosphate/ chitosan scaffold for periodontal tissue engineering. J. Mater. Sci. Mater. Med. 21 (2), 489–496. Lim, J.K., Saliba, L., et al., 2000. Normal saline wound dressing–is it really normal? Br. J. Plast. Surg. 53 (1), 42–45. Liu, Y., Griffith, M., et al., 2006. Properties of porcine and recombinant human collagen matrices for optically clear tissue engineering applications. Biomacromolecules 7 (6), 1819–1828. Lloyd, L.L., Kennedy, J.F., et al., 1998. Carbohydrate polymers as wound management aids. Carbohydr. Polym. 37 (3), 315–322. Lomova, M.V., Brichkina, A.I., et al., 2015. Multilayer capsules of bovine serum albumin and tannic acid for controlled release by enzymatic degradation. ACS Appl. Mater. Interfaces 7 (22), 11732–11740. Lord, M.S., Cheng, B., et al., 2011. The modulation of platelet adhesion and activation by chitosan through plasma and extracellular matrix proteins. Biomaterials 32 (28), 6655–6662. Losi, P., Lombardi, S., et al., 2004. Luminal surface microgeometry affects platelet adhesion in small-diameter synthetic grafts. Biomaterials 25 (18), 4447–4455. Lujan, T., 2010. Biomaterials science ME 491: lecture 5: natural polymers. From: http://www. biomechresearch.org/staff/lujan/teaching/Biomtrl_5%20Natural%20Polymers.pdf.

Introduction to biomaterials for wound healing

33

Mao, J.S., Zhao, L.G., et al., 2003. Structure and properties of bilayer chitosan-gelatin scaffolds. Biomaterials 24 (6), 1067–1074. Mathur, A., 2009. Regenerative wound healing via biomaterials. In: Gefen, A. (Ed.), Bioengineering Research of Chronic Wounds. Springer, New York, USA. Mathur, A.B., Tonelli, A., et al., 1997. The dissolution and characterization of Bombyx mori silk fibroin in calcium nitrate-methanol solution and the regeneration of films. Biopolymers 42 (1), 61–74. Maxey, C., Palmer, M., 1967. The isoelectric point distribution of gelatine. In: Cox, R. (Ed.), Photographic Gelatin II. Academic Press, London, UK. Mayet, N., Choonara, Y.E., et al., 2014. A comprehensive review of advanced biopolymeric wound healing systems. J. Pharm. Sci. 103 (8), 2211–2230. Medusheva, E.O., Filatov, V.N., et al., 2007. New medical materials with an integral lasting effect based on fibre-forming polymers. Fibre Chem. 39 (4), 268–271. Meyer-Blazejewska, E.A., Kruse, F.E., et al., 2010. Preservation of the limbal stem cell phenotype by appropriate culture techniques. Invest Ophthalmol. Vis. Sci. 51 (2), 765–774. Mi, F.L., Wu, Y.B., et al., 2002. Control of wound infections using a bilayer chitosan wound dressing with sustainable antibiotic delivery. J. Biomed. Mater. Res. 59 (3), 438–449. Michelacci, Y.M., 2003. Collagens and proteoglycans of the corneal extracellular matrix. Braz. J. Med. Biol. Res. 36 (8), 1037–1046. Miller, R.S., Steward, D.L., et al., 2003. The clinical effects of hyaluronic acid ester nasal dressing (Merogel) on intranasal wound healing after functional endoscopic sinus surgery. Otolaryngol. Head Neck Surg. 128 (6), 862–869. Mimura, T., Amano, S., et al., 2008. Tissue engineering of corneal stroma with rabbit fibroblast precursors and gelatin hydrogels. Mol. Vis. 14, 1819–1828. Min, B.M., Lee, G., et al., 2004. Electrospinning of silk fibroin nanofibers and its effect on the adhesion and spreading of normal human keratinocytes and fibroblasts in vitro. Biomaterials 25 (7–8), 1289–1297. Minoura, N., Aiba, S., et al., 1995. Attachment and growth of cultured fibroblast cells on silk protein matrices. J. Biomed. Mater. Res. 29 (10), 1215–1221. Miranti, C.K., Brugge, J.S., 2002. Sensing the environment: a historical perspective on integrin signal transduction. Nat. Cell Biol. 4 (4), E83–E90. Mishra, R., Banthia, A., et al., 2012. Pectin based formulations for biomedical applications: a review. Asian J. Pharm. Clin. Res. 5 (4), 1–7. Mogosanu, G.D., Grumezescu, A.M., 2014. Natural and synthetic polymers for wounds and burns dressing. Int. J. Pharm. 463 (2), 127–136. Mogosanu, G.D., Popescu, F.C., et al., 2012. Natural products locally modulators of the cellular response: therapeutic perspectives in skin burns. Rom. J. Morphol. Embryol. 53 (2), 249–262. Molan, P.C., 2006. The evidence supporting the use of honey as a wound dressing. Int. J. Low. Extrem. Wounds 5 (1), 40–54. Morelli, A., Chiellini, F., 2010. Ulvan as a new type of biomaterial from renewable resources: functionalization and hydrogel preparation. Macromol. Chem. Phys. 211 (7), 821–832. Morris, C.J., 2003. Carrageenan-induced paw edema in the rat and mouse. Methods Mol. Biol. 225, 115–121. Muangman, P., Opasanon, S., et al., 2011. Efficiency of microbial cellulose dressing in partial-thickness burn wounds. J. Am. Col. Certif. Wound Spec. 3 (1), 16–19. Mueller, A., 2005. Engineering biomedical materials from corn and wool. Chem. Eng. Prog. Alcht. Munarin, F., Tanzi, M.C., et al., 2012. Advances in biomedical applications of pectin gels. Int. J. Biol. Macromol. 51 (4), 681–689.

34

Wound Healing Biomaterials

Murakami, K., Aoki, H., et al., 2010. Hydrogel blends of chitin/chitosan, fucoidan and alginate as healing-impaired wound dressings. Biomaterials 31 (1), 83–90. Muzzarelli, C., Muzzarelli, R.A., 2002. Natural and artificial chitosan-inorganic composites. J. Inorg. Biochem. 92 (2), 89–94. Naimer, S.A., Chemla, F., 2000. Elastic adhesive dressing treatment of bleeding wounds in trauma victims. Am. J. Emerg. Med. 18 (7), 816–819. Nayak, S., Kundu, S.C., 2014. Sericin-carboxymethyl cellulose porous matrices as cellular wound dressing material. J. Biomed. Mater. Res. A 102 (6), 1928–1940. Nehrer, S., Chiari, C., et al., 2008. Results of chondrocyte implantation with a fibrin-hyaluronan matrix: a preliminary study. Clin. Orthop. Relat. Res. 466 (8), 1849–1855. Neuman, M.G., Nanau, R.M., et al., 2015. Hyaluronic acid and wound healing. J Pharm Pharm Sci. 18 (1), 53–60. Nicolai, J., Rakhorst, G., 2008. Introduction. In: Rakhorst, G., Ploeg, R. (Eds.), Biomaterials in Modern Medicine: The Groningen Perspective. World Scientific Publishing Co., Inc, New Jersey, USA. Nordback, P.H., Miettinen, S., et al., 2015. Chitosan membranes in a rat model of full-thickness cutaneous wounds: healing and IL-4 levels. J. Wound Care 24 (6), 245–246 248–251. O’Donovan, D.A., Mehdi, S.Y., et al., 1999. The role of Mepitel silicone net dressings in the management of fingertip injuries in children. J. Hand Surg. Br. 24 (6), 727–730. Obara, K., Ishihara, M., et al., 2005. Acceleration of wound healing in healing-impaired db/db mice with a photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2. Wound Repair Regen. 13 (4), 390–397. Ohtani, T., Mizuashi, M., et al., 2007. Cadexomer as well as cadexomer iodine induces the production of proinflammatory cytokines and vascular endothelial growth factor by human macrophages. Exp. Dermatol. 16 (4), 318–323. Opoku, G., Qiu, X., et al., 2006. Effect of oversulfation on the chemical and biological properties of kappa carrageenan. Carbohydr. Polym. 65 (2), 134–138. Ortega, M.R., Ganz, T., et al., 2000. Human beta defensin is absent in burn blister fluid. Burns 26 (8), 724–726. Padamwar, M.N., Pawar, A.P., et al., 2005. Silk sericin as a moisturizer: an in vivo study. J. Cosmet. Dermatol. 4 (4), 250–257. Panilaitis, B., Altman, G.H., et al., 2003. Macrophage responses to silk. Biomaterials 24 (18), 3079–3085. Parenteau-Bareil, R., Gauvin, R., et al., 2010. Collagen-based biomaterials for tissue engineering applications. Materials 3 (3), 1863–1887. Park, S.N., Kim, J.K., et al., 2004. Evaluation of antibiotic-loaded collagen-hyaluronic acid matrix as a skin substitute. Biomaterials 25 (17), 3689–3698. Park, S.N., Lee, H.J., et al., 2003. Biological characterization of EDC-crosslinked collagenhyaluronic acid matrix in dermal tissue restoration. Biomaterials 24 (9), 1631–1641. Park, S.U., Lee, B.K., et al., 2014. The possibility of microbial cellulose for dressing and scaffold materials. Int. Wound J. 11 (1), 35–43. Pasqui, D., Torricelli, P., et al., 2014. Carboxymethyl cellulose—hydroxyapatite hybrid hydrogel as a composite material for bone tissue engineering applications. J. Biomed. Mater. Res. A 102 (5), 1568–1579. Paul, W., Sharma, C., 2004. Chitosan and alginate wound dressings: A short review. Trends Biomater. Artif. Organs 18, 18–23. Pawar, S.N., Edgar, K.J., 2012. Alginate derivatization: a review of chemistry, properties and applications. Biomaterials 33 (11), 3279–3305. Pereira, C.S., Cunha, A.M., et al., 1998. New starch-based thermoplastic hydrogels for use as bone cements or drug-delivery carriers. J. Mater. Sci. Mater. Med. 9 (12), 825–833.

Introduction to biomaterials for wound healing

35

Pinchuk, L., 1994. Polyurethane degradation: effects on mechanical properties and carcinogenicity. In: Klitzman, B. (Ed.), Problems in General Surgery: Biomaterials. J.B. Lippincott, Co, Philadelphia, PA, USA. Pomin, V.H., Mourao, P.A., 2008. Structure, biology, evolution, and medical importance of sulfated fucans and galactans. Glycobiology 18 (12), 1016–1027. Popa, E., Reis, R., et al., 2012. Chondrogenic phenotype of different cells encapsulated in kappa-carrageenan hydrogels for cartilage regeneration strategies. Biotechnol. Appl. Biochem. 59 (2), 132–141. Price, R.D., Das-Gupta, V., et al., 2001. A study to evaluate primary dressings for the application of cultured keratinocytes. Br. J. Plast. Surg. 54 (8), 687–696. Qin, Y., Hu, H., et al., 2006. The conversion of calcium alginate fibers into alginic acid fibers and sodium alginate fibers. J. Appl. Polym. Sci. 101 (6), 4216–4221. Rabea, E.I., Badawy, M.E., et al., 2003. Chitosan as antimicrobial agent: applications and mode of action. Biomacromolecules 4 (6), 1457–1465. Rafat, M., Matsuura, T., et al., 2009. Surface modification of collagen-based artificial cornea for reduced endothelialization. J. Biomed. Mater. Res. A 88 (3), 755–768. Rama, P., Matuska, S., et al., 2010. Limbal stem-cell therapy and long-term corneal regeneration. N. Engl. J. Med. 363 (2), 147–155. Rao, S.B., Sharma, C.P., 1997. Use of chitosan as a biomaterial: studies on its safety and hemostatic potential. J. Biomed. Mater. Res. 34 (1), 21–28. Raphael, K.G., Marbach, J.J., et al., 1999. Self-reported systemic, immune-mediated disorders in patients with and without proplast-teflon implants of the temporomandibular joint. J. Oral Maxillofac. Surg. 57 (4), 364–370 discussion 370–1. Ratner, B., Hoffman, A., et al., 2013. Biomaterials Science: An Introduction to Materials in Medicine. Elsevier Academic Press, London, UK. Rinaudo, M., 2008. Main properties and current applications of some polysaccharides as biomaterials. Polym. Int. 57 (3), 397–430. Robson, M.C., 1997. Wound infection. A failure of wound healing caused by an imbalance of bacteria. Surg. Clin. North Am. 77 (3), 637–650. Rocha, P.M., Santo, V.E., et al., 2011. Encapsulation of adipose-derived stem cells and transforming growth factor-β1 in carrageenan-based hydrogels for cartilage tissue engineering. J. Bioact. Compat. Polym. 26 (5), 493–507. Rothwell, S.W., Sawyer, E., et al., 2009. Wound healing and the immune response in swine treated with a hemostatic bandage composed of salmon thrombin and fibrinogen. J. Mater. Sci. Mater. Med. 20 (10), 2155–2166. Ruszczak, Z., 2003. Effect of collagen matrices on dermal wound healing. Adv. Drug Deliv. Rev. 55 (12), 1595–1611. Raafat, D., von Bargen, K., et al., 2008. Insights into the mode of action of chitosan as an antibacterial compound. Appl. Environ. Microbiol. 74 (12), 3764–3773. Salbach, J., Rachner, T.D., et al., 2012. Regenerative potential of glycosaminoglycans for skin and bone. J. Mol. Med. (Berlin) 90 (6), 625–635. Santo, V.E., Frias, A.M., et al., 2009. Carrageenan-based hydrogels for the controlled delivery of PDGF-BB in bone tissue engineering applications. Biomacromolecules 10 (6), 1392–1401. Schultz, G.S., Barillo, D.J., et al., 2004. Wound bed preparation and a brief history of TIME. Int. Wound J. 1 (1), 19–32. Schwab, I.R., 1999. Cultured corneal epithelia for ocular surface disease. Trans. Am. Ophthalmol. Soc. 97, 891–986. Sedel, L., 2004. Biomaterials: medical viewpoint. From: http://atmsp.whut.edu.cn/resource/ pdf/4078.pdf.

36

Wound Healing Biomaterials

Senel, S., McClure, S.J., 2004. Potential applications of chitosan in veterinary medicine. Adv. Drug Deliv. Rev. 56 (10), 1467–1480. Senni, K., Pereira, J., et al., 2011. Marine polysaccharides: a source of bioactive molecules for cell therapy and tissue engineering. Mar. Drugs 9 (9), 1664–1681. Sezer, A., Cevher, E., 2011. Biopolymers as wound healing materials: challenges and new strategies. In: Pignatello, R. (Ed.), Biomaterials Applications for Nanomedicine. InTech, Inc. Sezer, A.D., Cevher, E., et al., 2008. Preparation of fucoidan-chitosan hydrogel and its application as burn healing accelerator on rabbits. Biol. Pharm. Bull. 31 (12), 2326–2333. Sezer, A.D., Hatipoglu, F., et al., 2007. Chitosan film containing fucoidan as a wound dressing for dermal burn healing: preparation and in vitro/in vivo evaluation. AAPS PharmSciTech 8 (2) Article 39. Shahverdi, S., Hajimiri, M., et al., 2014. Fabrication and structure analysis of poly(lactide-co-glycolic acid)/silk fibroin hybrid scaffold for wound dressing applications. Int. J. Pharm. 473 (1–2), 345–355. Shan, Y.H., Peng, L.H., et al., 2015. Silk fibroin/gelatin electrospun nanofibrous dressing functionalized with astragaloside IV induces healing and anti-scar effects on burn wound. Int. J. Pharm. 479 (2), 291–301. Sheridan, R.L., Morgan, J.R., et al., 2001. Biomaterials in burn and wound dressing. In: Severian, D. (Ed.), Polymeric Biomaterials. Marcel Dekker, New York, USA. Sheridan, R.L., Tompkins, R.G., 1999. Skin substitutes in burns. Burns 25 (2), 97–103. Shi, L., Yang, N., et al., 2015. A novel poly(gamma-glutamic acid)/silk-sericin hydrogel for wound dressing: synthesis, characterization and biological evaluation. Mater. Sci. Eng. C Mater. Biol. Appl. 48, 533–540. Sibbald, R., Leaper, D., et al., 2011. Iodine made easy. Wounds Int. 2 (2), S1–S6. Sierpinski, P., Garrett, J., et al., 2008. The use of keratin biomaterials derived from human hair for the promotion of rapid regeneration of peripheral nerves. Biomaterials 29 (1), 118–128. Silva, T.H., Alves, A., et al., 2012. Marine algae sulfated polysaccharides for tissue engineering and drug delivery approaches. Biomatter 2 (4), 278–289. Siritienthong, T., Ratanavaraporn, J., et al., 2012. Development of ethyl alcohol-precipitated silk sericin/polyvinyl alcohol scaffolds for accelerated healing of full-thickness wounds. Int. J. Pharm. 439 (1–2), 175–186. Siritientong, T., Angspatt, A., et al., 2014. Clinical potential of a silk sericin-releasing bioactive wound dressing for the treatment of split-thickness skin graft donor sites. Pharm. Res. 31 (1), 104–116. Siritientong, T., Aramwit, P., 2012. A novel silk sericin/poly (vinyl alcohol) composite film crosslinked with genipin: Fabrication and characterization for tissue engineering applications. Adv. Mater. Res. 506, 359–362. Sofia, S., McCarthy, M.B., et al., 2001. Functionalized silk-based biomaterials for bone formation. J. Biomed. Mater. Res. 54 (1), 139–148. Sparavigna, A., Fino, P., et al., 2014. A new dermal filler made of cross-linked and autocross-linked hyaluronic acid in the correction of facial aging defects. J. Cosmet. Dermatol. 13 (4), 307–314. Tabata, Y., 2009. Biomaterial technology for tissue engineering applications. J. R. Soc. Interface 6 (Suppl. 3), S311–S324. Tang, H., Zhang, P., et al., 2010. Antibacterial action of a novel functionalized chitosan-arginine against Gram-negative bacteria. Acta Biomater. 6 (7), 2562–2571. Teramoto, H., Kameda, T., et al., 2008. Preparation of gel film from Bombyx mori silk sericin and its characterization as a wound dressing. Biosci. Biotechnol. Biochem. 72 (12), 3189–3196.

Introduction to biomaterials for wound healing

37

Thomas, S., 2000a. Alginate dressings in surgery and wound management–Part 1. J. Wound Care 9 (2), 56–60. Thomas, S., 2000b. Alginate dressings in surgery and wound management: part 2. J. Wound Care 9 (3), 115–119. Thomas, S., 2000c. Alginate dressings in surgery and wound management: part 3. J. Wound Care 9 (4), 163–166. Thu, H.E., Zulfakar, M.H., et al., 2012. Alginate based bilayer hydrocolloid films as potential slow-release modern wound dressing. Int. J. Pharm. 434 (1–2), 375–383. Tomihata, K., Ikada, Y., 1997. In vitro and in vivo degradation of films of chitin and its deacetylated derivatives. Biomaterials 18 (7), 567–575. Tong, M., Tuk, B., et al., 2009. Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by a heparan sulfate glycosaminoglycan mimetic, OTR4120. Wound Repair Regen. 17 (6), 840–852. Toskas, G., Hund, R.-D., et al., 2011. Nanofibers based on polysaccharides from the green seaweed Ulva Rigida. Carbohydr. Polym. 84 (3), 1093–1102. Trumble, D.R., McGregor, W.E., et al., 2002. Validation of a bone analog model for studies of sternal closure. Ann. Thorac. Surg. 74 (3), 739–744 discussion 745. Tsai, I.L., Hsu, C.C., et al., 2015. Applications of biomaterials in corneal wound healing. J. Chin. Med. Assoc. 78 (4), 212–217. Ueno, H., Mori, T., et al., 2001. Topical formulations and wound healing applications of chitosan. Adv. Drug Deliv. Rev. 52 (2), 105–115. Ueno, H., Yamada, H., et al., 1999. Accelerating effects of chitosan for healing at early phase of experimental open wound in dogs. Biomaterials 20 (15), 1407–1414. Van den Kerckhove, E., Stappaerts, K., et al., 2001. Silicones in the rehabilitation of burns: a review and overview. Burns 27 (3), 205–214. Vasconcelos, A., Cavaco-Paulo, A., 2011. Wound dressings for a proteolytic-rich environment. Appl. Microbiol. Biotechnol. 90 (2), 445–460. Vasita, R., Katti, D.S., 2006. Nanofibers and their applications in tissue engineering. Int. J. Nanomed. 1 (1), 15–30. Vera, J., Castro, J., et al., 2011. Seaweed polysaccharides and derived oligosaccharides stimulate defense responses and protection against pathogens in plants. Mar. Drugs 9 (12), 2514–2525. von Recum, A.F., LaBerge, M., 1995. Educational goals for biomaterials science and engineering: prospective view. J. Appl. Biomater. 6 (2), 137–144. Voytik-Harbin, S.L., Brightman, A.O., et al., 1998. Application and evaluation of the alamarBlue assay for cell growth and survival of fibroblasts. In Vitro Cell. Dev. Biol. Anim. 34 (3), 239–246. Wang, Z., Zhang, Y., et al., 2014. Exploring natural silk protein sericin for regenerative medicine: an injectable, photoluminescent, cell-adhesive 3D hydrogel. Sci. Rep. 4, 7064. Watanabe, R., Hayashi, R., et al., 2011. A novel gelatin hydrogel carrier sheet for corneal endothelial transplantation. Tissue Eng. Part A 17 (17–18), 2213–2219. Wei, L., Tang, J., et al., 2010. Investigation of the cytotoxicity mechanism of silver nanoparticles in vitro. Biomed. Mater. 5 (4), 044103. Whelan, J., 2002. Smart bandages diagnose wound infection. Drug Discov. Today 7 (1), 9–10. Wright, B., Cave, R.A., et al., 2012. Enhanced viability of corneal epithelial cells for efficient transport/storage using a structurally modified calcium alginate hydrogel. Regen. Med. 7 (3), 295–307. Wright, K.A., Nadire, K.B., et al., 1998. Alternative delivery of keratinocytes using a polyurethane membrane and the implications for its use in the treatment of full-thickness burn injury. Burns 24 (1), 7–17.

38

Wound Healing Biomaterials

Yao, K., Mao, J., et al., 2002. Chitosan/gelatin network based biomaterials in tissue engineering. Biomed. Eng. Appl. Basis Commun. 14 (03), 115–121. Ye, J., Yao, K., et al., 2006. Mesenchymal stem cell transplantation in a rabbit corneal alkali burn model: engraftment and involvement in wound healing. Eye (London) 20 (4), 482–490. Ye, K., Sullivan, K., et al., 2011. Encapsulation of cardiomyocytes in a fibrin hydrogel for cardiac tissue engineering. J. Vis. Exp. 55, 3251. Yeh, L.K., Chen, Y.H., et al., 2009. The phenotype of bovine corneal epithelial cells on chitosan membrane. J. Biomed. Mater. Res. A 90 (1), 18–26. Yuan, H., Song, J., et al., 2006. Antioxidant activity and cytoprotective effect of kappacarrageenan oligosaccharides and their different derivatives. Bioorg. Med. Chem. Lett. 16 (5), 1329–1334. Zanette, C., Pelin, M., et al., 2011. Silver nanoparticles exert a long-lasting antiproliferative effect on human keratinocyte HaCaT cell line. Toxicol. In Vitro 25 (5), 1053–1060. Zaoming, W., Codina, R., et al., 1996. Partial characterization of the silk allergens in mulberry silk extract. J. Investig. Allergol. Clin. Immunol. 6 (4), 237–241. Zhang, H., Zhang, K., et al., 2015a. Comparison of two hyaluronic acid formulations for safety and efficacy (CHASE) study in knee osteoarthritis: a multicenter, randomized, double-blind, 26-week non-inferiority trial comparing Durolane to Artz. Arthritis Res. Ther. 17, 51. Zhang, N., Gao, T., et al., 2015b. Environmental pH-controlled loading and release of protein on mesoporous hydroxyapatite nanoparticles for bone tissue engineering. Mater. Sci. Eng. C Mater. Biol. Appl. 46, 158–165. Zhang, W., Zhong, D., et al., 2013. Effect of chitosan and carboxymethyl chitosan on fibrinogen structure and blood coagulation. J. Biomater. Sci. Polym. Ed. 24 (13), 1549–1563. Zhong, S.P., Zhang, Y.Z., et al., 2010a. Tissue scaffolds for skin wound healing and dermal reconstruction. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2 (5), 510–525. Zhong, W., Xing, M.M., et al., 2010b. Nanofibrous materials for wound care. Cutan. Ocul. Toxicol. 29 (3), 143–152. Zhou, G., Sun, Y., et al., 2004. In vivo antitumor and immunomodulation activities of different molecular weight lambda-carrageenans from Chondrus ocellatus. Pharmacol. Res. 50 (1), 47–53. Zou, S.B., Yoon, W.Y., et al., 2013. Cytotoxicity of silver dressings on diabetic fibroblasts. Int. Wound J. 10 (3), 306–312.